Anti-angiogenic therapies that block vascular endothelial growth factor (VEGF) signaling have become a cornerstone of cancer treatment, yet their clinical utility remains limited by suboptimal responses and inevitable drug resistance. A new study published in Science Bulletin provides the first systematic single-cell analysis of the pancancer angiogenic landscape, revealing an unexpected culprit behind treatment failure: tumor-educated pericytes.
Researchers from Sun Yat-sen University Cancer Center and collaborators analyzed 1.24 million individual cells from 381 tumor samples across 13 common cancer types, including breast, colorectal, gastric, liver, and lung cancers. Their comprehensive atlas uncovered that pericytes—contractile cells that wrap around blood vessels—and their secreted factors PGF and ANGPT2, strongly correlate with tumor angiogenesis.
The study identified a previously undocumented population of tumor-educated pericytes, termed MCAM+ immature pericytes (imPCs), as the primary cellular source of PGF and ANGPT2. These cells are shaped by dysregulated Notch signaling and hypoxic stress within the tumor microenvironment. Through extensive in vitro and in vivo experiments, the researchers demonstrated that MCAM+ imPCs drive alternative angiogenic pathways that bypass VEGF inhibition, making them a major contributor to resistance against anti-VEGFR therapies such as bevacizumab. Importantly, clinical data from ovarian cancer, urothelial cancer, and glioblastoma patients treated with bevacizumab confirmed that higher levels of MCAM+ imPCs were significantly associated with worse overall survival and progression-free survival, validating their clinical relevance in treatment resistance.
To address this challenge, the research team developed a novel therapeutic strategy using MCAM-targeting antibody-drug conjugates (MCAM ADC). By eliminating pro-angiogenic MCAM+ imPCs specifically, the MCAM ADC disrupts the cellular source of PGF/ANGPT2 -- pericytes. When combined with anti-VEGFR therapy, this dual EC/PC inhibition approach demonstrated superior anti-angiogenic effects and tumor control in multiple mouse models of breast, renal, and lung cancers, compared to either treatment alone.What’s more, the humanized version of the MCAM ADC, AMT-253, is currently being evaluated in a Phase I first-in-human clinical trial (NCT05906862).Biosafety evaluations showed that the MCAM ADC exhibited excellent tolerability, with no significant impact on body weight, blood cell counts, liver or kidney function, or blood-brain barrier integrity, supporting its translational potential for clinical applications.
In summary, this study constructed the first pan-cancer pro-angiogenic atlas, reinterpreted the mechanism underlying resistance to anti-angiogenic therapy, and proposed a dual inhibition strategy targeting both endothelial cells and pericytes, offering new insights for the development of more effective anti-tumor therapies.
Professors Xu Ruihua, Liu Zexian, and Luo Huiyan from the Sun Yat-sen University Cancer Center are the co-corresponding authors of the paper, while Dr. Zheng Yongqiang, Dr. Sun Hui, Dr. Fu Zhe, Dr. Chen Haojie, and Dr. Cai Guangyao are the co-first authors.
This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0501600), National Key R&D Program of China (2021YFA1302100), National Natural Science Foundation of China (82503704, 32370698, 82321003, 82173128), Young Talents Program of Sun Yat-sen University Cancer Center (YTP-SYSUCC-0029), the Chih Kuang Scholarship for Outstanding Young Physician-Scientists of Sun Yat-sen University Cancer Center (CKS-SYSUCC-2024009), the Postdoctoral Science Foundation of China (2024M763801, GZB20240907) and Guangdong Esophageal Cancer Institute Science and Technology Program (M202503).
Science Bulletin
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